Can a Senolytic Vaccine Slow Ageing? Dr David Scieszka on Senescent Cells and Longevity

Speaker A: 00:00:00

Foreign.

Speaker B: 00:00:05

Welcome to Beyond Longevity, the podcast that explores not just how we age, but how we can build a longer, healthier future for ourselves. What if we could teach the immune system to remove some of the damaged cells that contribute to the aging process?

My guest today is David Scieszka, a biomedical scientist, computational biologist, and the founder and CEO of Vertical Longevity Pharmaceuticals, or Velo Pharma for short. He holds a PhD in biomedical sciences as well as an MBA. His interest in longevity began while serving in the US Army.

From here, he moved into laboratory science, computational biology, and eventually biotech entrepreneurship. His company is now developing a senolytic vaccine.

The idea is to help the immune system recognize and clear senescent cells, the dysfunctional so called zombie cells that accumulate as we age. The company's first focus is the vasculature, the network of blood vessels that carries blood around the body.

More specifically, they are looking at atherosclerosis, where blood builds up inside the arteries. But this episode is about much more than one vaccine.

We take a step back and look at why so much promising longevity science struggles to make it from the lab into real world medicine.

We talk about where AI can generally help, what animal studies can really tell us, and what it takes to turn a scientific idea into a treatment that could one day reach patients. And running through the conversation is a bigger question. If we do find a way to slow parts of the aging process, who gets access to it first?

Can longevity medicine ever really become longevity for all? Hi, Dr. David, thank you so much for joining me today on Beyond Longevity.

You've taken a rather unusual route into this field, from US army through several different areas of science to founding a longevity biotech company. Behind all that journeys seems to be an ambition that goes well beyond developing one successful treatment.

But before we get into the science, I want to start with you. How did you get from the US army to studying aging? And when did this become something you felt personally driven to?

Speaker A: 00:02:53

Thanks for the question. It was actually my first foray into longevity.

When I was in the US army, we were on a deployment, and as PSYOP specialists, we were tasked with interviewing local populations. And so I was, you know, a glorified census taker saying, what's your name? How old are you? What do you need?

Do you need schools, hospitals, a toothbrush? And so I noticed this trend that people outside of cities, more in the rural areas, they were accelerating their aging process.

They would report they were 35, but they would look 55. And so they were accelerating their aging. And it was largely due to A lack of things like toothbrushes or access to good food or healthcare.

And then we would go into the cities, we would do the same process, and they would report they were 35, but they would look 25. And so this, to me, was a real world example of people altering their ability to age or altering their aging trajectory. So I thought, this is it.

We figured it out. I've got to go back, get out of the army, and start allowing people access to healthcare. It was a lot more complicated than I originally anticipated.

That's largely a political issue that I wasn't able to address. I found that my real bent was towards science, and so I found got into biotech instead.

And from there on, it's been a journey always focused on aging ever since.

Speaker B: 00:04:17

That's quite incredible. I want to get into some of the points that you've mentioned a little bit later on, but what particular area of aging inspired you to delve in deeper?

Was it the fact that, like you said, some people aged quicker than others, or was there something else that caught your attention as such?

Speaker A: 00:04:38

Yeah, it was kind of a mix of the current technologies that were coming out at the time. I was taking a look at nanotechnology, and it was in its burgeoning stages. And then CRISPR was really a hot topic.

And so it was either go the biotech route or the nanotech route, because in my mind at the time, it was either can we deliver drugs? Or can we alter the biology from, say, a CRISPR gene editing standpoint?

And so I ended up going the biotech route, not just because nanotech was in its early stages, but also because there was an incredible program that accepted me as a young college student. And that was a very rigorous program. I have a large amount of respect for the professors there and the mentors there. It was very collaborative.

You look back sometimes and you are very thankful for the opportunities. And it seems like destiny, but it's one of those things. Maybe it is what we make of it.

But I couldn't have asked for a better introduction to science, really than that biotech program at Cal State all those years ago.

Speaker B: 00:05:38

That's so nice when you have inspirational people around you that not only encourage your passions, but to actually bring them to light in the first place and draw them out.

You've worked both as a wet lab scientist studying biology through physical experiments, and also as a computational biologist, like you said, using data to understand what is happening across complex biological systems. How has seeing the signs from both sides changed the way you think about aging? Or has it changed the way you think about aging?

Speaker A: 00:06:13

Yeah, probably. For better and for worse. I gotta credit my mentor, Marcelo Freire. He's at the J. Craig Venter Institute.

While I was going to Cal State San Marcos, I was applying for internships in research institutes. And it just so happened that he and I merged our personalities.

And so he was the one that originally said, okay, now you've generated the data, figure out how to analyze it. And so that was the beginnings of that. And what's happened since has been probably a very deep understanding of what's wrong and what can go right.

Garbage in, garbage out is the thing we say in computer science. And it. It kind of describes the scientific landscape as a whole as well, Biotech.

If you reanalyze a lot of these large datasets, you can find that your interpretations can be different just by the simple changing of a threshold here or maybe a different model being applied there.

And so if you can change drastically the outcomes with a couple of lines of code, really the conclusions that we're finding need to be taken with a grain of salt as well.

So until we're able to have a consistent framework across biological analyses, and until we can apply these with biological context, I think that we're going to continually see this fragmented or this fragmentation in our conclusions on aging itself. But the biology is not changing. It's just our ability to analyze it that is really what's changing here.

Speaker B: 00:07:43

Do lab experiments and computational analysis sometimes point towards different conclusions completely?

Speaker A: 00:07:51

Yeah, Exactly. During my PhD, I took a couple of approaches to try to figure out what the best course of action was.

And if I was analyzing data and using, say, five different models to analyze it, and they all would consistently report the same gene or protein or transcript, then we had high confidence that it was valid, it was true biology that was occurring, as opposed to a lot of the times. There's a very complex set of tools that needs to go into these analyses.

So I don't throw stones at anybody who only does one model, finds the conclusion, and then publishes it. I don't think that's data manipulation.

I think it's probably a lack of time, which we all are very limited on, of course, and really this thoroughness that should be able in the coming years, there's an ability of us to be more thorough with our analyses either because the tools themselves are becoming easier to use. And so maybe we can all have a much more consistent, thorough framework that we're applying.

Speaker B: 00:08:48

We have a lot of discussions, you know, on beyond longevity, AI versus I don't want to say the real world, but, you know, versus sort of wet lab results and progress and how they need to work hand in hand in order to move forward in a realistic way. How much do you see AI being helpful to those studies rather than maybe not a hindrance, but where can it not be applied?

And so I'm asking for the present, but. And where do you see it going in the future?

Speaker A: 00:09:22

Yeah, and the translational aspect and the ability of AI to be useful. Two very important points. I can definitely start with the AI for the AI and the ability of where it can be helpful.

We can talk about specifically single cell analyses like proteomics, where you measured proteins, or single cell RNA sequencing, where you measured the RNA transcripts, which then get turned into proteins downstream. They, they both have their different functionalities and use cases.

But the expression profile, the abundance of proteins within each individual cell is how we classify it, how we identify it as a cell type itself. That's how we say this is a cardiac cell versus a liver cell, is by the abundance of the proteins. And.

And in aging, as you can imagine, a lot of these cells start expressing proteins at altering abundances relative to their normal expression profiles.

And so we could be miscategorizing, misidentifying cells simply by the nature of biology itself, diverging from this natural course that we call it healthy aging. So if they're increasing their expression of protein X, we could be calling it a liver cell, where it's actually a cardiac cell.

And that's probably too blunt of an example because it's really the difference between say, a vascular cell versus a smooth muscle cell or something much more closely linked with each other.

But still, that ability needs to be taken into account before AI can be as helpful as it can be without the ability to have these data sets, which is why SendNet exists, actually.

This is over 200 million have been invested into senescent cell profiling across proteomics, transcriptomics, and then trying to standardize this process. Until we can get those data sets out there, AI is going to be providing us results that we have to then analyze again with biological context.

Otherwise it becomes a little bit meaningless. False positives, false negatives, et cetera. I do think AI is currently powerful.

I don't think that we're going to see this AI revolution that a lot of people are calling for until we can have that overhaul of our data itself going probably as far back as we started sequencing. I mean, it's going to be a large endeavor, to be sure, for sure.

Speaker B: 00:11:44

As we all know that AI is only as good as the data has to work from. But when do you think that sort of bit of AI will catch up with the real world and it will actually be a real support and help.

We're talking about years, decades. What do you think?

Speaker A: 00:12:04

Big fan of some companies that are already doing this.

So in silicone medicine, many people have probably heard of in silicone medicine, but Alex, the CEO, he's actually a longevity guy, turned into this drug discovery mobile of course, but they generate data internally, they predict internally, they validate internally.

They're taking the process as kind of from a philosophical standpoint, we can either generate the communities ourselves and watch them expand out into the population, or we can just assume that the population is going to change this modality. What they're doing it in Silico and many others, they're not the only ones. They're starting this process over.

They're creating these databases so that they can predict better. And I think that that's a fantastic approach if you have the money for it.

But it's, it's also incredibly expensive having all of these automated processes. How many millions of dollars and and to assume everybody can do that's probably a non starter.

So maybe, maybe decades is hopefully sooner though I don't want to be a downer. Hopefully sooner than decades.

Speaker B: 00:13:10

Listen, you've got to hope you never know. This AI is moving at such rapid speed that it is hard to keep up with it and its potential.

You've spoken about wanting to extend healthy life not just for a small group of people, the ones that can afford what you just mentioned, these multimillion dollar projects, you've wanted to extend that as widely as possible. And you also use the principle of find somebody to help and repeat. What is the deeper motivation behind your work overall?

What are you ultimately trying to make possible?

Speaker A: 00:13:50

I trained for over 10 years to stay in academia as a professor. I did not necessarily expect to move into industry immediately. And probably the underlying principle would be to help as many people as possible.

That that's why we do research to try to find these basic underlying principles that we can then expand into broader therapeutic potential. But our mission is longevity for all. And that's really started from how aging is the greatest source of human suffering.

Beyond mosquito borne illnesses, beyond anything else, aging is the greatest source of human suffering.

And so if we can target aging itself as not necessarily a disease, because I would never call my parents diseased and I don't know what else to call it, but as a modality that we could intervene across potentially, then we can really start impacting the broadest amounts of humans possible in a positive way. The idea with longevity for all is this also has to be from a business case.

We have to be able to develop something that has a very wide safety window. And by that I mean low doses are not going to hurt people. High doses are not going to hurt people either.

Typically in therapeutic development, they are developed for a very narrow set of the population to impact a single disease. If you can positively impact that disease from a therapeutic standpoint, great.

We wanted to flip that script and say, let's start from first principles. What is underlying a lot of these age related diseases? The vasculature. The vasculature is the plumbing between all organs.

If that is dysfunctional, it's reducing the capacity of all organs. So if we can reverse vascular dysfunction, let's see how many diseases we can impact. And that has been incredibly fruitful.

So our, our mission of longevity for all, starting with vascular dysfunction. And I, I do apologize for getting out of soapbox here. The, the.

Starting with vascular dysfunction, we could have gone after it with an antibody, which is incredibly expensive, or we could have gone after it with CAR T cells, again, ridiculously expensive. We chose the vaccine modality because it can be produced for under a dollar a dose.

We wanted to be able to meet the Gates foundation benchmark for global distribution regardless of socioeconomic disposition or geographic location. We wanted to be able to get this into the hands of everybody who needs it.

And so what we're really doing is kind of that second philosophical principle. We're generating that community of longevity for all, hoping that we can bring in as many people as possible and then expanding it out.

We are the change that we want to see in the world. We're building that future that we want to be a part of and that's the broader mission is just to help as many people as possible.

So we had to strategize from the start because if we had selected antibodies, we, it wouldn't have been as impactful. And so that's really.

You have to strategize, you have to see the finish line and then back up to the starting line and then strategize how to get there.

Speaker B: 00:16:54

Before we get to your company and the incredible vision and mission behind it, I just want everyone to understand the very basics of what you're doing.

You've, as you just said, compared the vascular system to the body, body's plumbing because it carries oxygen and nutrition to almost every tissue and Helps remove waste. Can you explain the analogy of what begins to go wrong with this biological plumbing as we age?

Speaker A: 00:17:25

Yeah, that's a really good point. So the vascular system is a high sensitivity interface. Really, I can use the plumbing algae too.

But the inside of veins and arteries, there's a single cell layer called the endothelium. And this is the interface for signaling vascular tone.

The ability to deliver nutrients and oxygen, like you said, is reliant on this single cell lining layer of your plumbing.

When they start transforming into a dysfunctional state called senescence, which is a hallmark of human aging, they lose the ability to, to function like they originally would. That starts happening around age 25 in all people. It, it can be earlier for some, it can be later for others.

But you start to accumulate these senescent cells and thank God, I mean, it's an anti cancer mechanism. So we could either have them be cancerous vascular cells or senescent vascular cells. So I'm glad that they went that way.

But they persist and they accumulate and they transform their neighboring cells senescent and they excrete inflammation into the circulation, impacting those organs as well. So it's a feed forward loop, gradual senescent endothelial cell accumulation.

And by removing those cells, your stem cells are then able to replace them, Restoring your vasculature, restoring your plumbing to the state of age that it should be, as opposed to an accelerated aging state. So in a nutshell, the cells we target are like cracks that accumulate in, in the plumbing.

What our vaccine really does is allow the body to repair its pipes.

And so if we think about the plumbing as the thoroughfare between all organs, the ability of each organ to receive nutrients and oxygen is depleted as well as removing metabolic waste is depleted.

So by repairing these cracks in the pipes, you can then allow the organs to function at a much younger state where they normally would function at without these dysfunctional cracks in the plumbing.

Speaker B: 00:19:29

What is a senescent cell? Why does the body create them? And what can be the negative impact on the body of a senescent cell?

Speaker A: 00:19:39

And so senescent cells are pro inflammatory state of cell cycle arrest.

So they're no longer dividing, but they're still metabolically active and excreting pro inflammatory molecules into the extracellular milieu into their neighboring cells. So it's pro inflammatory dysfunctional because it's no longer working like it was supposed to.

So say from a liver cell, the accumulation of senescent cells reduces the liver's ability to function, not only because the senescent Cells are no longer functioning like liver cells, but their neighboring cells are also inflamed because of the senescent cells. So that's a pro inflammatory state of cell cycle arrest. And it occurs many different ways.

Largely we describe DNA damage being an upstream outcome before senescent cell transformation. Because for those keeping track at home, the cell cycle is comprised of different G1s, G2m. There are just different processes within a cell cycle.

And at specific junctions of that cycle, the body has checkpoint checkers. So it, it'll verify that the DNA is fidelitous, that the DNA is lacking damage. And if everything's a go, then it proceeds to the next step.

But if at 1g 1s or g 2m, if at either one of those stages, the body or the cell rather recognizes that there is something awry, there's too much DNA damage, then it stops the cell cycle and exits into this state of senescence, which is quite different from apoptosis or necrosis. Apoptosis is a very regulated cell death. It recognizes that it's not functioning the way that it's supposed to.

And so the signals from the external as well as the signals from the internal say we have to collapse and die in a very regulated way so we don't cause inflammation or secondary autoimmunity. Necrosis, on the other hand, is where the cell cannot do that regulated process.

It still dies, but it's more of a bubbling of the cell membrane, potentially an explosion of the cell membrane or at least a ripping of the cell membrane, and then things leak out into the surrounding area, which can cause an increase in inflammation, increase in the likelihood of secondary autoimmunity, and in some cases because inflammation causes cancer, then we can talk about cancer as well. From necrosis. Senescent cells try to avoid all of that. They should go apoptosis, but. But I'm glad that they also don't go necrotic.

I think that that would be a higher order risk, but then potentially we would be aging at a slower rate. So it's all about hazard ratios. What's going to impact the body negatively longer? Yeah, that's a very complex question.

Speaker B: 00:22:24

Well, you've made it sound easy to understand for people that have no concept of it at all. Let's talk about this vaccination you are developing.

So if the problem is that certain damaged cells remain in the body and begin affecting the tissue around them, your proposed solution is to teach the immune system to recognize them and remove them. Is that basically how the vaccine works?

Speaker A: 00:22:53

Pretty much, yeah. And then One thing on the senescent cells as well, I probably should have mentioned that there are lysosomes.

So inside of every cell there are different organs, we call them organelles.

And lysosomes specifically are acid filled sacs that we use to degrade many things, misfolded proteins, things that they, the cell brings in from the outside. Lysosomes, kind of like a garbage compactor.

And with age those permeabilize and so it's leaking acid into the cell, causing DNA damage, causing mitochondrial dysfunction, causing epigenetic modifications. And so this is upstream of senescent cell transformation as well. And to your point, yes, it is basically right on the vaccine.

We and others have found that senescent cells in the vasculature upregulate, a target that we can vaccinate against. And what it really is doing, your body used to be able to clear these cells very well, especially when you're below the age of 25.

And so what we're really doing is allowing the immune system to remember what it had always done before by clearing out these cells, it's then restoring the vasculature to the state that it should be at as opposed to this pro inflammatory, dysfunctional, vascular, dysfunctional state that it exists in today. But yeah, that's basically it. We're enabling the body to repair itself.

Speaker B: 00:24:11

And how do you envision this to work? Is it a one off vaccination? Do you need boosters? Do older people need more of it than, and younger? At what age do you start?

Gosh, all these questions. Pick one and we'll just work our way through them. But it's, it's just so fascinating.

You know, these are all the things I'm sure, not just going through my mind when we hear this.

Speaker A: 00:24:36

Not at all, not at all. We tested preclinically in naturally aged mice because of the age difference. And this is for the biologists and those who heard of thymic involution.

And so the ability of the body to respond to a vaccine declines with age. So if it works at an aged time point, it'll work every year before that. It'll work better actually every year before that.

And so that's why we tested in aged mice. Now we're testing in aged primates for the exact same reason.

If we can positively impact the aged primate, a human relevant animal, then we know that it will positively impact every age below that as well. Or it will definitely cause a vaccine response we anticipate based off of our vaccine platform, a three dose series once a month.

So it's hopefully seamlessly integrated into the current way that we vaccinate. With the three dose series, it's not too fast, it's not too slow.

We actually anticipate based off the platform that you could extend that out maybe once every two months for that three dose series just to form this long term memory. We do anticipate boosters being necessary for some, but we're hoping that that's a smaller portion of the population.

The primate study will show that actually the effects themselves, if they're too fast then they could be detrimental and if they're too slow, the FDA might not appreciate it. It would cost more money for approval. I'm leaning towards slow.

So I hope that these effects are longer lasting and that the immuno memory will be long term so that we do not have to be boost. But that's definitely has to be shown in the primates.

Speaker B: 00:26:12

How does the immune system learn which cells to attack? Very unscientific terms, but are you not teaching it from scratch but just sort of giving it a push and reminding it of what it used to do?

Would that then make the immune system remember what to target?

Speaker A: 00:26:32

The way that we're we're approaching this is we're using what's called a virus like particle. And if you can visualize the COVID virus, it looks almost exactly identical.

And then those spike proteins on the COVID virus, that is what we're adhering to the virus like particle, that's what the immune system rips off and then starts generating antibodies against that is then going to bind to our target cell. And the immune system recognizes bound antibody for then immune mediated cytotoxic cell clearance.

So it's called a D C C antibody dependent cell clearance.

So what we're really doing is saying these cells here exclusively in the vasculature are expressing this target and only after they transform senescence that's going to reduce the safety hazards because we're not targeting any of the other senescent cells as well, including the heart, the brain, the testes, anything like that.

Yes, we are definitely re engaging the immune system to do what it did before, but kind of in a roundabout way as before it would recognize that a cell is dysfunctional, so it would clear senescent cells wherever it could.

This is exclusively in the vascular system because of potential safety concerns where you target all senescent cells, which there are approaches to do that. And I think that their patient populations are going to be unfortunately narrowed just by the broader Effect itself.

And we've seen this historically from senolytics, senescent cell clearing, small molecules like nabitoclax A B T263, they were targeting mitochondrial stress and they were clearing out far too many cells. So we're really targeting exclusively the vasculature just to reduce those safety concerns for longevity for all really.

Speaker B: 00:28:17

So what I'm hearing is, is that it is specifically targeted to the cardiovascular cells. Looking ahead, does that though mean you could also use it to target other.

Speaker A: 00:28:29

Cells, senescent cells, and more specifically the vasculature? We definitely don't want to target the cardiovascular cells, but just the plumbing leading to the heart, that's what we're targeting as well.

And yes, we definitely could. So there's really clever approaches right now.

Targeting misfolded proteins that get expressed on the surface, that's a lot more difficult because for various reasons. But yes, this could be applied to potentially anything that you want to target yourself with or an external virus.

You could definitely do that with a virus like particle.

Speaker B: 00:29:02

And just to clear up any confusion, because I know there is a small number of people, but nonetheless a number of people that are very worried that vaccines can somehow change the DNA, the RNA and especially ever since the COVID jabs, you know, it's. There are all these conspiracies, theories flying around. How can you assure the public that this is not what is happening?

Speaker A: 00:29:33

And regardless of my personal opinions on vaccine safety and things of that nature, we avoid the entire conversation. So many people are worried about adjuvants, which is the thing that you include in the value of vaccines to elicit an immune response.

It boosts the immune response recognition. This is a self adjuvant. The immune system recognizes it as a virus itself. So we don't need any adjuvants as well.

We're not using any integrative mRNA, which regardless of whether or not that does occur, we're not using mRNA. It's a capsid, basically an empty shell of a virus. So it's not even self replicating once we're injecting it. So there's no integration with the DNA.

All it's doing is going into your body. Your immune system says that looks like a virus, they grab it, they then generate antibodies against our targets.

So the antibody generation is all that occurs as opposed to any sort of potential DNA integrations, any sort of adjuvant issues. Multi dosing is taken out of that because we know the dosing that is necessary from previous primate trials as well.

Well, three Dose series is enough to generate a long term immune response. And so that's gonna be placating a lot of the major issues.

But I, I also do feel like from a sociopolitical standpoint, we're gonna see a resurgence in the idea that vaccines are safer than originally anticipated. Just as a societal pendulum swings back and forth, we're swung right now towards fear.

And I, I can understand that with the recent Covid occurrence and. But we're probably going to swing towards baseline again, where vaccines are necessary part of life to prevent things like Ebola.

Speaker B: 00:31:14

You know, there are many proposed ways of intervening in aging, changing metabolism or cellular programming, things like that. Why did you choose senescent cell clearance? Did you believe it's the best way to affect aging?

Or was it sort of just simply one of the most practical places to begin?

Speaker A: 00:31:35

Yeah, when I was working as a fellow for the Life Science Angels, I was screening companies and so I had to develop a longevity investment thesis. And so we can think about these things in short term, medium term, and long term approaches in the shortest term.

Just like you said, senescent cells are a very easy lever to pull. They're a very easy modality to target. This is going to extend longevity escape velocity as the next iteration.

Mitochondrial function, metabolic disorder, very complex. It's a lot harder to target. And so I do see those being a little bit more midterm.

They'll be the post senolytic age in, in my mind anyway, the post senolytic age will be more mitochondrial and then long term is definitely going to be the partial epigenetic reprogramming. Those will be the moonshot effects, or at least what we see today is a moonshot approach.

Because the dosing is so complex, the dosing between the eye is going to be different from the nose, different from the gums, different from every organ. So we have to get that right and right for every person.

Speaker B: 00:32:38

Not an easy task ahead. Lots of work for you to still be doing. Just to be clear, the vaccine is a fantastic idea.

And as compelling as it is, the treatment is still pre clinical, though. You've just started your primate study. Very exciting.

This is sort of the stage where we need to separate what the research has demonstrated from what you hope the treatment may eventually achieve. What exactly has been shown so far?

Speaker A: 00:33:11

We benefit from external validation. And as a bioinformatician, I appreciate where those limitations lie. So.

So in human atherosclerosis, which is the clogging of arteries, there have been groups that took postmortem tissue from the arteries themselves and stained them for senescent cells. They lit up like Christmas trees. So there are definitely an abundance of senescent cells in human atherosclerosis.

We've also had previous oncology clinical trials for cancer oncology clinical trials against our exact same protein targets.

So we know the safety window from previous oncology trials and we know that senescent cells exist in human atherosclerosis and many other diseases as well. The translatable aspect, I think is important from a health span aspect as well as a lifespan and disease altering aspect.

So really the primate trial is designed to identify a broad swathe of diseases that we could potentially, potentially target, find the strongest signal and pursue that initial FDA clearance for then downstream patient population expansion. So get over the finish line and expand from there. But the really critical aspect of this is they're already geriatrics.

So we have the rare opportunity of actually turning this into a lifespan. One of the first longevity therapeutic lifespan studies in primates.

Shout out to Adam Sandman for doing the first one in rapamycin, but we're doing the second one. And these are geriatric animals where we're starting. So it's a very rare opportunity.

And if this, as we anticipate it, does, if we show healthy lifespan extension through measures of frailty and arthritis and bone density and organ fitness and things of that nature and show lifespan extension, governments are going to take notice. This is going to become a research priority. The, the society will also start to take notice that these do work.

It depends, of course, on the modality itself and the person at play, because people are, we say this in pharmacology. Humans are terrible models for other humans. This is just the way we are. Beautifully complex, but also beautifully complexly frustrating.

It's so what works for me probably doesn't work for you. And you've probably seen this in a lot of your investigations as well.

Speaker B: 00:35:35

What is the single most important question the primate study is designed to answer? Is there even a single most important question?

Speaker A: 00:35:46

The most exciting outcome that we're measuring is the unclogging of arteries, the reversal of atherosclerosis. So it is the leading cause of global mortality still, unfortunately, even with amazing advancements in the field.

And so if we can reverse atherosclerosis, that's just one aspect. There's downstream outcomes.

I mean, we have the ability to measure a thousand proteins every month, so we can get longitudinal organ functional analyses, which is similar to what aging clocks are attempting to do. Organ fitness across the board but we're also measuring markers of kidney disease, markers of metabolic disorder, I mean, you name it.

DEXA scans for bone quality, also arthritic markers. And so what we're really trying to do is reverse atherosclerosis and also measure the ability to extend health span healthy lifespan.

Speaker B: 00:36:40

So not to be, not to be too negative, but longevity research has produced extraordinary findings in labs and animal studies. But relatively few treatments have made the leap into routine clinical practice. Why is the translation so difficult?

Speaker A: 00:37:00

Yeah, that is such a fun question and I agree with you. So we've cured mouse Alzheimer's in mice. We've cured it. You know, there's, we haven't done it in humans.

Same thing with, just like you're saying, a lot of these longevity, they don't translate as effectively. And I think that there's brilliant scientists who are working on modeling why it doesn't work once you make that jump from mouse to human.

But I, I do want to say that when we investigate mice, they're in sterile environments and they're at 25 degrees Celsius, which is not thermo neutral for them. They are constantly shivering, they're cold. And so when that, that changes their immune system and their responses.

So when we cured Mouseheimer's, we cured it in a shivering mouse in a sterile environment. That signaling is going to be necessarily different in humans.

And so when we, we talk about this translational aspect, there's brilliant work being done by Tuck Finch and many others in the environmental toxicology field. My previous PI at University of New Mexico, Matt Campen, he was trying to take a look at these longevity interventions in real world scenarios.

What happens after a wildfire event? If you take these analytics, are they dangerous? Largely, the answer is yes.

The, the response was actually inverted from what we've seen canonically in the longevity field after you introduce real world settings to these animals. And that was worrisome, I would say, but also kind of the impetus for this wide breadth of safety window.

If we're targeting something so narrow and we're doing it in mice, then of course you have to hit a moving target from a moving target when you try to translate this into humans. But also the, the signaling is different. I mean the networks are different between humans and mice. I mean that goes without saying.

The cycles, estrocycle versus menstrual cycle in female mice versus women, different. And so even those endocrine, these hormonal signaling processes are dramatically different with humanized mice.

But that's more the humanized immune system as well. And so there's going to be these approaches, but those are still held in sterile environments and still at 25 degrees.

And so until we can model this appropriately, the differences and then bring things into real world scenarios, we will probably be affronted with this translational hazard.

But still, I understand it's incredibly expensive to run the studies that we already do, so I can't imagine how much more expensive it would be if you had to add on three separate studies for every single one study that we're running now. It's just, it could be financially unfeasible. But what do you think?

You've, you've probably talked to a lot of people about the translational aspect too. Have you found anything?

Speaker B: 00:39:45

As you said, you know, it's, it's just very hard because at the end of the day, a human is a human and you can only do so much testing, you know, in the labs and all that.

But this conversation is reminding me of is how many people are working obviously not just within the same field, but even on the same biomarkers or in general issues that we have of whatever relates to aging.

And we've just had on the founders of a company, you know, Lingevity, who also deals with dying cells, though they, as I'm sure you know, they're developing a drug or trying to develop a drug, should I say, to stop necrotic cell death, whereas you are trying to clear cells that remain alive but have become senescent. Do you think that there can ever be one best way to intervene in aging?

Or will meaningful progress in the field depend on several different treatments and companies solving different parts of the problem problem and then coming together?

Speaker A: 00:40:56

Yeah, I think just like you said, the many different companies being synergistically effective, but also the personalization. I'm a huge fan of longevity clinicians because they do take a personal look at a lot of their patients and they have to.

I, I completely understand that. But the, the prescription for one person is going to be different from another as well. Kevin White out of Oklahoma, phenomenal guy.

We just met at the age meeting, American association of Aging in Utah, and he said he prescribed a patient a social media fast because their cortisol levels were skyrocketing. It's simple. It sounds too simple to work, but it's elegant because it did work. I mean, it's just one of those things.

And so these multifaceted aspects. If, if you say, have a family history of liver dysfunction, liver therapeutics are going to be the way to go.

If you're in the case of David Sinclair and you have a history of cardiac disease, statins are the way to go. Currently we're fixing that, but statins are the currently the way to go. So this personalized aspect, I think that's the power of AI as well.

Once we can have all of these therapeutics on the market and we can have a personalization aspect, there could be a better prescribed therapy for you that is multifaceted or maybe it'll be a single. It probably just depends person to person. But do you see that's where the AI is coming to.

Speaker B: 00:42:20

I guess so. It's, you know, AI is just such a mind blowing field that God knows where it can lead us to.

I mean it's done amazing things, you know, like you said, the CRISPR and the protein fold and all that. So yeah, if used wisely and well, it can only improve anything that we humans can dream and think of.

I think, you know, this whole field of academia and industry that you've touched upon. I just also want to mention that not only have you completed a PhD in biomedical science, but at the same time you're also doing an mba.

I understand why my wife says it.

Speaker A: 00:43:02

Was because the PhD wasn't hard enough. It's, yeah, it's, it's a little bit more complex. I, I've kind of approached life the same way that I approached education.

And I don't know if, if other people do this the same. We anticipate the future and then we try to prepare for it in whatever ways that we can.

So when I saw that computer science was going to be of course, the way of the future, I got an undergrad in biotech and started learning computer science. Almost completed a, a degree in computer science as well. Same thing with the PhD. I wanted to either do an MBA, PhD or something else.

And I talked to a phenomenal advisor who said, do you really want to be bedside with patients for six years? And I said no, not really. And he said, okay, what do you really want to do? And I said, well, bringing therapies to people, I guess.

And you said, all right, think about the mba. And then when we started doing vaccine, that solidified that trajectory.

But it was through the guidance of others really that I was able to, I didn't even manifest it myself really.

It was just more of talking to people, figuring out from people far smarter than me, far far more experienced than I was what they would recommend, and then receiving that information, kind of pruning off what was unapplicable and then internalizing what really did make sense for my specific trajectory, that personalization aspect. And do you tend to have a lot of people with many different degrees on your podcast too? MD, PhDs, things like that?

Speaker B: 00:44:33

Well, you know, it depends because there are a lot of people that are really, you know, into academia and all that, and they have accumulated quite a few letters after their name. But many have pivoted, you know, into industry, which is not always easy, I think.

And I know you've spoken about how difficult it was for you in the beginning, speaking to investors, not knowing exactly, you know, what to ask for, how much money to ask for and all that. Tell our listeners a little bit about that because we have a lot of listeners that are on either side of the fence.

Either they are investors or they are founders.

Speaker A: 00:45:13

I would say to all of the entrepreneurs out there, thick skin is the way to go. Perseverance is something that we can control.

Speed is something that we can sometimes control, but perseverance is definitely something we can control.

And so if, if we have the ability to go through, say an incubator or an activator or an accelerator so that we can all get to the same level of understanding and then learn where good advice and bad advice are. Because advice are like eyeballs. Everybody's got them, but I mean, they don't always see clearly.

And so it's, it's really up to us to be able to figure out what does apply. From the investor standpoint, it really depends.

You have to find somebody who's excited about your tech, either as a generalist or in the specific avenue that you're approaching. And then their check size also matters.

If you're raising a pre seed, don't go after series A investors unless you're trying to build that relationship long term. If you need cash now, your. Your time could be more effectively spent elsewhere. Also the idea of the type of fund it is.

So some investor funds have a life cycle, 10 year life cycle.

And if you're receiving an investment towards the back end of that, that's a critical point because they will need that money back for their limited partners by the end of that life cycle of the investment fund. Some companies really have the screws put to them because the life cycle of the fund is ending.

Some investors need to have a board seat, some investors don't. And so all of these different aspects are critical questions while you're forming that relationship for entrepreneurs.

But from the investor side, I don't think I'll ever become an investor, but I would definitely let people Know as soon as I was able to all of these different requirements that I have. Yes, we have five years left in our life cycle. I have a fiduciary responsibility to my limited partners to gain award seats.

If that's unacceptable, we just, we can go our separate ways. Happy to introduce you to other people but that kind of thing. Yeah, I wish it was an easy process but it's, we're still learning.

I, I, I don't think that I will ever stop learning because just like human psychology and, and the idea of all of these different longevity aspects. Community affects longevity, green plants affect longevity. Same thing with investors.

There's a thousand different investors who are all perfect for us and a hundred thousand investors who for one reason or another are not. And I think it's just that perseverance aspect that, that really separates us from say some people that have flared out.

But that's not to say I think the perseverance is probably something that all entrepreneurs should strive to achieve.

Speaker B: 00:47:53

Oh absolutely. For sure. What should a scientist or first time founder have clearly worked out and mapped out before approaching an investor?

Speaker A: 00:48:05

Oh, and that's, that's really interesting. So there are investment funds for every Stage Evolution Foundation. Dr. Adeye met him there. Fantastic individual.

They have a pathway if you just have an idea. And that's not even the only one. There are multiple granting organizations as well as venture capital funds that will fund join Just ideas.

If you're at the preclinical mouse stage or cell culture stage, there are venture capitalists for you, grants for you as well. As an entrepreneur, it's more important to find those specific appropriate venture capitalists or grants because they're out there for them.

Maybe good science and an ability to explain it simply, otherwise no one's going to understand.

I actually had to find out that the first investors that we talked to didn't understand longevity and they thought that we were trying to do everything simultaneously. They said we were trying to boil the ocean. I said no, no, we're trying to go after one indication.

Our primate study is only going to be monitoring all of these because of the broad therapeutic potential. We're not trying to do all of these at once. That would be $500 million right out the gate. We're not doing that.

But we had to learn how to frame our story, which is something the Socratic triangle or the rhetorical triangle. Audience message speaker they all have to be in line otherwise something's going to get lost.

Our message was incorrect from the get go and so we had to tailor it more appropriately. And that's something that first time founders can definitely learn.

Speaker B: 00:49:35

We know you're not trying to boil the ocean, but nonetheless, how do you make sure that the original mission survives that process?

Speaker A: 00:49:45

It's woven into our very nature. It's impossible for me to do otherwise. And I've surrounded myself with like minded individuals who feel similarly.

When I was first interviewing our CSO positions, I found many people who saw dollar signs in their eyes. And that's, that's okay. Everybody's motivated by different things. Completely understand that.

When I met our cso, she goes, I don't care about any of the dollars that you just told me. How many people can we save? And I said potentially billions. She goes, I'm in. That's it. I'm.

And so we found each other through this longstanding interview process. It'll be the same thing with all future investors moving forward. Many of the people that we're talking right now, they have a dual bottom line.

Of course they're responsible for returning investment, but they're concerned about human impact. And that's. My bottom line is people. The money will come because it's a longevity company. But my bottom line is absolutely people.

And so we have to just continually surround ourselves with people who understand that too.

Speaker B: 00:50:47

It's lovely to hear that. Lovely makes it sound a bit condescending. And I really don't mean it in that way. I really mean it in a.

It's a very humbling way to look at what you're doing and the incredible goal you're trying to achieve. The idea behind it should always be the wish and the desire to help people improve their lives, any shape or form.

But of course it's a very expensive business to be in and money is a big driver, for better or worse.

But I think it's really refreshing to hear what's at the core of your company, that a serious company with serious goals can still be altruistic as its North Star. Where do you see the longevity medicine in 10 years, sort of over the next decade? What do you realistically expect to happen.

Speaker A: 00:51:44

With the recent approvals of either longevity, I would probably call them longevity adjacent drugs. So ozethic, of course, approaches many different things, age related diseases.

But I mean, metformin, you know, rapamycin, they've been prescribable for long. Aspirin, I mean, cheese. Many of these things that are preventing some aspects of age related mortality.

The next iteration for longevity escape velocity is probably going to be a targeted therapeutic only because we can optimize 95% of this with lifestyle factors. Community sleep is medicine, food is medicine if done right. Exercise is definitely medicine.

But it's got that bell shaped curve where too much of it can also impact negatively. So I mean all of these things are like 95% of it.

But then afterwards, to reach that next step of longevity escape velocity, we'll need some sort of therapeutic and that'll probably persist us for that 10 year window where something else will be improved and that'll extend us for that next 10 years.

It could be some sort of mitochondrial aspect perhaps it's something that we don't even talk about, like the vaults, which is just a different organelle that nobody even talks about. We didn't learn about it in biology, but it exists in every cell and it probably has longevity implications.

So maybe something that we don't even foresee is going to be in there.

Speaker B: 00:53:03

Well, you heard about here first is all I can say. Listen, Dave, thank you so much. What an interesting and insightful conversation.

We covered so many, you know, different areas and only scratched the surface. I always ask my guest five rapid fire questions. So what's the single best piece of advice you would give your younger self?

Speaker A: 00:53:25

You've got this. Don't stop.

Speaker B: 00:53:28

Name one habit everyone should adopt for a longer, healthier life.

Speaker A: 00:53:32

Probably with the current state of affairs. Eating healthier.

Speaker B: 00:53:35

If you weren't in longevity science, what career would you have chosen?

Speaker A: 00:53:40

I wanted to be a physicist, I really did.

Speaker B: 00:53:43

Quite a few people have said that actually. It's interesting, I mean considering you could say anything. But there were a couple that wanted to be physicists.

What microdose habit, five minute routine or small daily action yields outsized longevity benefits?

Speaker A: 00:53:59

I would either say coffee, but that's probably too, too specific to myself. Maybe a five minute walk during the middle of the day when we are starting. So used to sitting all the time, just stand up, walk around.

Speaker B: 00:54:12

Both very valid and good points, I have to say. Coffee and walking. And last but not least, what's the craziest longevity myth you've encountered and is there any truth to it?

Speaker A: 00:54:24

I met somebody recently who's using ozone, treating patients with ozone. And in the lab we regularly use ozone to cause massive neural inflammation. And so that was incredibly surprising.

And she said she's been doing it for 24 years. And I said whoa, that's okay. I can't speak to the legitimacy here because I don't believe there is.

But I would just warn everybody out there, whoever you talk to in the longevity field, try to cross validate any of these therapeutics or use these clinicians with. If you can't read the science, find somebody who can. This is your life.

I mean, you have to be able to determine whether or not something good or bad is going into you.

Speaker B: 00:55:07

You'd think so isn't. David, thank you so much for coming on Beyond Longevity. It was such a pleasure to talk to you.

What this conversation really shows is how difficult it is to turn good longevity signs into something that can actually help people. Finding the right biological target is only the beginning. You then have to prove that the science works outside the lab.

You have to understand the data, get through animal studies, clinical trials, regulation and funding. And even if you succeed, there's still another who gets access to it. David Sin.

The senolytic vaccine is still at an early stage and there's a lot that still needs to be proven. But the idea behind it is fascinating.

Instead of waiting for individual diseases to appear, could we one day target some of the biology that makes us more vulnerable to those diseases in the first place? And if we can, can we make those treatments available to to everyone rather than only to the people who can afford them?

Thank you so much for joining me on Beyond Longevity today. Please rate, review and subscribe. Thank you.